HLA-DQ Recognition of Gluten
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| Illustration of HLA-DQ with peptide in the binding pocket |
HLA DQ Receptor with bound peptide and TCR |
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Understanding DQ Haplotypes and DQ isoforms
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| DQ haplotypes |
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Each individual has 22 pairs of autosomes. The HLA complex in humans is a large region, ~3 million nucleotides, on chromosome 6, within this region there are a large number of genes. The DQ represent 2 genetic loci that lie next to each other. One gene is called DQA1 and the other is called DQB1. There are many alleles at each genetic locus.
Further information: HLA-DQ, HLA-DQA1, HLA-DQB1
DQ antigen, a cell surface receptor, is composed of two polypeptide subunits. There are dozens of alleles at each locus and many create unique subunit isoforms. There are a large number of possible combinations. Evolution of humans has limited the most common isoforms. These are more common isoforms encoded by haplotypes, almost all of the time, one passed without change from a persons mother and father from conception. Each allele at each locus has an official name. For the alpha subunit the names are given by the gene-alleles. For example the major DQ1 alleles are given as DQA1*0101, *0102, *0103, *0104. DQ1 refers to the DQ α1 groups of isoforms (historically by serotype) which is the 01 portion of the allele number, the last two digits identify a specific allele in that group. All other DQ serotypes refer to beta chain groups - DQ2, DQ3-(DQ7, DQ8, DQ9), DQ4, DQ5, DQ6. A common way to write a phenotype (both alleles a person has) as DQA1*0101/*0102. This is not enough information to identify a persons isoforms. We also need information about beta chain, the best way to do this is to refer to common haplotypes. HLA-DQ haplotypes are commonly written in a style: HLA-DQA1*0101:DQB1*0501. When considering a persons haplo-phenotype the form DQA1*0102:DQB1*0602/DQA1*0501:DQB1*0201 is the same as DQA1*0102/*0501 DQB1*0602/*0201. When drawn out the form can be used to identify all potential isoforms. (See image below)
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There are many potential DQ isoforms as a result of cis- and trans-haplotype pairing (see image on left). Of course the cis-haplotypes are more common. Typically most individuals can produce 4 isoforms, but the 2 isoforms tend to be the most abundant. There are instances where this may not be true, such as when the two betas or two alphas are very similar in structure. Most important with regard to isoforms - different subunit isoform pairings can result in the binding of different foreign or self antigens. From a disease defense perspective the more different kinds of peptides that can be presented, the more likely the immune system will detect pathogens and remove them quickly. As a consequence the HLA genes are kept extremely variable in most mammalian populations relative to other genes. |
DQ2.5 and gluten sensitivity
For coeliac disease however there appears to be one isoform that has a higher role. This isoform is DQ α5-β2 (DQ2.5). Because the beta chain is β2, historically it has been called DQ2. Not all DQ2 isoforms are pathogenic, but at least 2 appear to be more associated with disease. DQ2.5 isoform is not rare, 25% of Americans Caucasians carry the isoform, whereas >90% of people with coeliac disease carry the isoform. DQ2 is also increased in gluten-sensitive idiopathic neuropathy. The DQA1*0501:DQB1*0201 haplotype is the most frequent source of DQ2.5 isoform called DQ2.5cis. It is found in almost all celiacs and the haplotype is frequently called, also, DQ2.5 haplotype.
25% of celiacs are DQ2 homozygotes (HLA DQB1*02 homozygotes), only a small percent of these do not bear DQ2.5cis. This minority are invariably DQA1*0201:DQB1*0202 (DQ2.2cis homozygotes).
The majority of DQ2 homozygotes are homozygotes of the DQ2.5 haplotype or DQ2.5 and DQ2.2 haplotypes. These DQ2 homozygotes tend to show increased mucosa damage and degradation and are at greatest risk for severe complications of coeliac disease, refractory disease, and enteritis associated T-cell lymphoma (EATL).
Further information: DQ2.5, DQ2.2, DQ2 and coeliac disease, HLA DR3-DQ2
Risk for disease tends to be carried in families because of the DQ2.5cis encoding haplotypes. Atypically about 3% of coeliacs get DQ2.5 isoform as a result of trans-chromosomal encoding. This can occur because one DQ haplotype, DQA1*0505:DQB1*0301 (DQ7.5) produces an alpha chain in which the variable portion relative to DQA1*0501 is chopped off during processing to DQ heterodymer.
Therefore it can produce the α5 subunit. The DQ2.2 haplotypes provide the β2 subunit, and consequently DQ7.5/DQ2.2 phenotype creates the DQ2.5trans isoform.
The DQ isoform has a complex genetic involvement in coeliac disease. And these involvements explain the majority of disease. One other haplotype exists that is associated with disease, although not as common in Europe, DQ8 is found to be involved in coeliac disease in peoples were DQ2 is not present. DQ8.1 haplotype encodes the DQA1*0301:DQB1*0302 haplotype and represents the overwhelming majority of all DQ8. DQ2.5 is generally highest in northern, islandic Europe, and the Basque of Northern Spain. Phenotype frequency exceeds 50% in certain parts of Ireland. DQ8 is extremely high in Native Americans of Central America and tribes of Eastern American origin, fortunately most of these peoples have retained a maize based diet.
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HLA-DQ proteins present polypeptide regions of proteins of about 9 amino acids and larger in size (10 to 14 residues in involved in binding is common for gliadin) to T lymphocytes. Gliadin proteins can be adsorbed by APC. After digestion in the lysozomes of APCs, glaidin peptides can be recycled to the cell's surface bound to DQ, or they can be bound and presented directly from the cell surface. The major source of inflammatory gluten is dietary gluten. Optimal reactivity of gliadin occurs when the protein is partially digested by small intestinal lysozyme and trypsin into proteolytic digests. These polypeptides of gluten can then make their way behind the epithelial layer of cells (membrane), where APCs and T-cells reside in the lamina propria. (See: Underlying conditions)
The APC bearing DQ-gliadin peptide on the surface can bind to T-cells that have an antibody-like T-cell receptor the specifically recognized DQ2.5 with gliadin. The complex (APC-DQ-glaidin) thus stimulates the gliadin specific T-cells to divide. These cells cause B-cells that recognize gliadin to proliferate. The B-cells mature into plasma cells producing anti-gliadin antibodies. This does not cause coeliac disease and is an unknown factor in idiopathic disease. Enteropathy is believed to occur when tissue transglutaminase(tTG) covelantly links itself to gliadin peptides that enter the lamina propria of the intestinal villus. The resulting structure can be presented by APC (with the same gliadin recognizing DQ isoforms) to T-cells, and B-cells can produce anti-transglutaminase antibodies. This appears to result in the destruction of the villi. The release of gliadin by transglutaminase does not lessen disease. When tTG-gliadin undergoes hydrolysis (steals a water to cut the two apart), the result is deamidated gliadin. Deamidated gliadin peptides are more inflammatory relative to natural peptides. Deamidated gliadin is also found in foods that have added gluten, such as wheat bread, food pastes.
The major gluten proteins that are involved in coeliac disease are the α-gliadin isoforms. Alpha gliadin is composed of repeated motifs that, when digested, can be presented by HLA-DQ molecules. DQ2.5 recognizes several motifs in gluten proteins, and therefore HLA-DQ can recognize many motifs on each gliadin (see Understanding DQ haplotypes and DQ isoforms on the right) However, numbers of different proteins from the grass tribe Triticeae have been found to carry motifs presented by HLA DQ2.5 and DQ8. Wheat has a large number of these proteins because its genome contains chromosomes derived from two goat grass species and a primitive wheat species. The positions of these motifs in different species, strains and isoforms may vary because of insertions and deletions in sequence. There are a large number of wheat variants, and a large number of gliadins in each variant, and thus many potential sites. These proteins once identified and sequenced can be surveyed by sequence homology searches.